Basics of Medical Genetics - Buzhiyevska T.I. 2001

Hereditary diseases
Hereditary diseases of the urinary system

In addition to Urinary Tract malformations associated with chromosomal syndromes or occurring as isolated congenital anomalies of genetic or teratogenic origin, as well as Polycystic Kidney Disease and nephrological symptoms accompanying nearly all Metabolic Disorders, hereditary Tubulopathies warrant special attention.

These disorders occur in children of various ages much more frequently than commonly assumed. They often remain undiagnosed, ultimately leading to disability and premature death.

Primary tubulopathy is characterized by severe osteopathy, nephrocalcinosis, and Nephrolithiasis. The primary clinical manifestations of this pathology include polyuria, polydipsia, hyposthenuria, alkaline urine reaction, pronounced metabolic acidosis, significant Blood bicarbonate deficit, and blood ionogram abnormalities (hypokalemia, hypocalcemia, hyponatremia, hypochloremia, etc.). Affected children experience physical growth retardation. The Pathogenesis of hereditary tubulopathy is rooted in a genetically determined inability of the Kidneys to lower urine pH.

Two Types of tubular lesions are distinguished: 1) proximal, which determines a defect in bicarbonate reabsorption; and 2) distal, characterized by impaired transport of H+ ions across The Cell membranes of the distal tubules.

Secondary hyperparathyroidism leads to elevated phosphate levels. The most common forms of this pathology are outlined below.

Nephrolithiasis is a genetically determined disorder of calcium METABOLISM. Calcium salts are excreted in the urine. This condition leads to hypocalcemia, Osteomalacia, delayed Cartilage ossification, and cartilage thickening. The most critical symptom is latent or overt acidosis, which requires active correction. Nephrolithiasis management requires high fluid intake along with magnesium and phosphate salts to improve the solubility of calcium salts. In the presence of edema, potassium salts should be used instead of NaCl. In cases of significant osteomalacia, calcium and calciferol (up to 50,000 IU daily) are administered.

Adult Renal Tubular Acidosis (Butler–Albright syndrome) presents with lower limb deformity and extremity pain. It is characterized by The Development of nephrocalcinosis, Pyelonephritis, and distal-type tubulopathy. Physical growth retardation is commonly observed. This disorder is inherited in an AD or AR pattern (various forms).

Infantile renal tubular acidosis (Lightwood syndrome) typically first appears at 1 to 18 months of age, often coinciding with the Introduction of complementary foods (cottage cheese, cow's milk). Symptoms include apathy, thirst, weakness, vomiting, exicosis, polyuria, weight loss, and frequently convulsions and hypokalemia. The inheritance pattern is XR or sex-restricted (70% of patients are male). The prognosis is favorable.

De Toni–Debré–Fanconi Syndrome (renal/tubular Rickets) manifests at any age, most frequently during the 2nd year of life. The child becomes lethargic, presenting with subfebrile Temperature, thirst, polyuria, and muscular hypotonia. Additional features include Osteoporosis, tubular bone deformity, spontaneous fractures, as well as glucosuria, Aminoaciduria, and phosphaturia. An AD inheritance pattern with variable expressivity is characteristic. Currently, this syndrome is also considered within the group of mitochondrial disorders.

Alport syndrome (chronic hereditary hematuric nephritis) begins in childhood and manifests with weakness and frequent acute respiratory infections complicated by Hematuria. The clinical course is torpid, with late and infrequent symptoms including arterial Hypertension and edema. The syndrome is characterized by congenital cataracts, nystagmus, myopia, and—most importantly—Hearing loss, spherophakia, anterior lenticonus, and tapetoretinal degeneration. Biochemical findings include hyperaminoaciduria and hyperaminoacidemia, hyperaminoaciduria alone, or a depleted amino acid spectrum in blood and urine. Six types of the syndrome are recognized, inheriting via AD, AR, or XR patterns. Mutations in Collagen genes have been identified. Tubulopathy in this syndrome is secondary.

Renal glucosuria is characterized by urinary glucose excretion (up to 50–60 g per day). Blood glucose concentration remains normal, and glucose tolerance curves are normal. Type A glucosuria involves a lowered renal threshold for glucose and decreased reabsorption, whereas Type B is accompanied by a lowered renal threshold with normal reabsorption. Both AD and AR inheritance patterns have been described.

Renal diabetes insipidus manifests between 3 and 6 months of life with marked diuresis, tendency toward constipation, vomiting, and elevated body temperature. Thirst may be absent in infants, but polyuria is pronounced: infant diuresis can occasionally reach 2 L per day. Complications include salt fever, convulsions, and hypotrophy. Physical growth retardation is noted. The renal tubules fail to respond to the antidiuretic hormone of the neurohypophysis. This disorder is inherited in an XR pattern. Treatment is symptomatic and includes dietotherapy (restricting dietary salt and protein while enriching the diet with fats and CARBOHYDRATES). Dehydration must be minimized. Diuresis is reduced using hydrochlorothiazide.

Phosphate Diabetes (vitamin D-resistant rickets, Albright–Butler–Blumberg syndrome) manifests when children begin to walk, toward the end of the first year of life. Affected children develop lower limb deformities and a waddling gait. In severe cases, toddlers are unable to walk. Hypophosphatemia develops, and alkaline phosphatase activity increases sharply. Affected children exhibit short stature and frequent bone fractures. The disease is caused by impaired phosphate reabsorption in the renal tubules. Aminoaciduria and glucosuria are absent. An XD inheritance pattern with 100% penetrance is characteristic.

Treatment involves prolonged administration of high doses of calciferol, accompanied by monitoring of blood calcium and phosphate levels. Favorable effects are achieved with 1,25-dihydroxycholecalciferol and tachysterol, which improve intestinal calcium absorption, as well as the intake of mineral Water containing inorganic phosphates. Secondary tubulopathies develop in many hereditary metabolic disorders.